Characterization of renin mRNA expression and enzyme activity in rat and mouse mesangial cells

Andrade, Antero Silva Ribeiro de; Casarini, Dulce Elena; Schor, Nestor; Boim, Mirian Aparecida

doi:10.1590/s0100-879x2002000100003

Cited by 23 publications

(25 citation statements)

References 21 publications

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“…Gene and protein expression of angiotensinogen (Aogen), renin and ACE has been reported in cultured glomerular mesangial cells [12][13][14][15][16][17][18][19][20][21][22][23][24] and podocytes. [25][26][27][28] Mesangial expression of Aogen and ACE has also been documented in renal tissue sections.…”

Section: Intrarenal Raasmentioning

confidence: 99%

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

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The renin-angiotensin-aldosterone system (RAAS) has a central function in the regulation of blood pressure. Aliskiren, the first direct renin inhibitor to be approved for the treatment of hypertension, blocks the RAAS at its point of activation. As renin inhibition acts at the top of the RAAS cascade, this mechanism has been proposed to offer advantages over existing modes of RAAS blockade. The RAAS is also considered to be a major factor in the pathogenesis of many renal diseases, especially diabetic nephropathy (DN), the main cause of end-stage renal disease. Existing therapies to block the RAAS slow the progression of DN, but they do not halt the disease. Therefore, more effective modes of interventions are needed. Studies to determine the efficacy of aliskiren in human renal disease are in progress. This review summarizes in vivo studies in which the efficacy of aliskiren was tested in experimental models of renal disease, and presents in vitro studies that provide insights into the possible mechanisms by which aliskiren confers renoprotection in animals. These works are discussed in the framework of the intrarenal RAAS and suggest that aliskiren may act by unique renoprotective mechanisms. Keywords: aliskiren; kidney; mechanism; nephropathy; renin INTRODUCTIONThe renin-angiotensin-aldosterone system (RAAS) is an ancient pathway 1 that has evolved into a central mechanism by which mammalian blood pressure (BP) and fluid homeostasis are regulated. Research in this field started with the discovery in 1898 by Tigerstedt and Berman 2 that a renal extract when injected into rabbits induced a rapid increase in systemic BP. Subsequent work over many years established the RAAS as a pivotal contributor to cardiorenal diseases. Hence, inhibitors of the middle and distal portions of the RAAS pathway, angiotensin-converting enzyme (ACE) inhibitors (ACEI) and AT 1 receptor blockers, respectively, have become mainstay therapies for treating hypertension. In 2007, aliskiren, the first direct renin inhibitor (DRI), was approved for the treatment of hypertension. This heralded the therapeutic control of BP by inhibiting the RAAS at its first and rate-limiting step. However, RAAS blockade is also effective for treating renal disease 3-6 and the efficacy of aliskiren for this purpose is currently being investigated. Accordingly, the subject of this review is to summarize the preclinical evidence for renoprotection by aliskiren, and to discuss recently published information on the possible mechanism(s) for these benefits. As it is well recognized that there is a tissue as well as circulating RAAS, 7 the preclinical actions of aliskiren will be discussed in the context of the intrarenal RAAS and the potential for its inhibition by aliskiren.

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Section: Intrarenal Raasmentioning

confidence: 99%

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

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“…Interestingly, it has been demonstrated that glomerular mesangial cells express mRNA for renin, AGT, and ACE (1). Moreover, mesangial cells in culture are able to synthesize and secrete renin, prorenin, and ANG II and contain both the AT 1 receptor and the prorenin/renin receptor (1,20,22,23). This cell type has been shown to produce extracellular matrix and contributes to progression of glomerulosclerosis (10).…”

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confidence: 99%

“…A homolog of ACE, termed ACE2, has been recently discovered, which hydrolyzes ANG I to ANG (1)(2)(3)(4)(5)(6)(7)(8)(9) and ANG II to ANG(1-7) (8). ANG II exhibits the majority of its well-known physiological effects via the angiotensin type 1 (AT 1 ) receptor.…”

mentioning

confidence: 99%

Activation of renal renin-angiotensin system in upstream stimulatory factor 2 transgenic mice

Shi¹,

Nikolic²,

Liu³

et al. 2009

American Journal of Physiology-Renal Physiology

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S. Activation of renal renin-angiotensin system in upstream stimulatory factor 2 transgenic mice. Am J Physiol Renal Physiol 296: F257-F265, 2009. First published November 12, 2008 doi:10.1152/ajprenal.90493.2008.-Previously we demonstrated that upstream stimulatory factor 2 (USF2) transgenic (Tg) mice developed nephropathy including albuminuria and glomerular hypertrophy, accompanied by increased transforming growth factor (TGF)-␤ and fibronectin accumulation in the glomeruli. However, the mechanisms by which overexpression of USF2 induces kidney injury are unknown. USF has been shown to regulate renin expression. Moreover, the renin-angiotensin system (RAS) plays important roles in renal diseases. Therefore, in the present studies the effects of USF2 on the regulation of RAS in the kidney as well as in mesangial cells from USF2 (Tg) mice were examined. The role of USF2-mediated regulation of RAS in TGF-␤ production in mesangial cells was also determined. Our data demonstrate that USF2 (Tg) mice exhibit increased renin and angiotensin (ANG) II levels in the kidney. In contrast, renal expression of other components of RAS such as renin receptor, angiotensinogen, angiotensin-converting enzyme (ACE), ACE2, angiotensin type 1a (AT 1a) receptor, and AT 2 receptor was not altered in USF2 (Tg) mice. Similarly, mesangial cells isolated from USF2 (Tg) mice had increased renin and ANG II levels. Mesangial cells overexpressing USF2 also had increased TGF-␤ production, which was blocked by small interfering RNA-mediated renin gene knockdown or RAS blockade (enalapril or losartan). Collectively, these results suggest that USF2 promotes renal renin expression and stimulates ANG II generation, leading to activation of the intrarenal RAS. In addition, renin-dependent ANG II generation mediates the effect of USF2 on TGF-␤ production in mesangial cells, which may contribute to the development of nephropathy in USF2 (Tg) mice.transforming growth factor-␤ THE RENIN-ANGIOTENSIN SYSTEM (RAS) is a multistep enzymatic cascade to produce a family of angiotensin peptides that control blood pressure and fluid homeostasis. The components of the RAS, including angiotensinogen (AGT), renin, and angiotensin-converting enzyme (ACE), are present systemically for endocrine production of angiotensin (ANG) II. AGT, the only known precursor to ANG II, is constitutively secreted from hepatocytes as well as other cell types and generally is considered to be non-rate-limiting in the production of systemic ANG II (28). AGT is cleaved by the aspartyl protease renin to generate ANG I. For systemic production of ANG II, renin synthesis and release from juxtaglomerular (JG) cells of the afferent arteriole is the rate-limiting step. Hydrolysis of the COOH-terminal amino acids of ANG I by ACE results in the formation of ANG II, the primary peptide of the RAS with biological activity. A homolog of ACE, termed ACE2, has been recently discovered, which hydrolyzes ANG I to ANG(1-9) and ANG II to ANG(1-7) (8). ANG II exhibits the majority of its well-known phys...

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“…While this interpretation does not exclude the possibility that aliskiren could bind to renin that may be present in podocytes (5), mesangial cells (1,21), or trafficking through the mesangial matrix, the data indicate that for aliskiren to accumulate in glomeruli, the presence of renin is not required. This interpretation is consistent with recent findings in mice (11) showing that renal accumulation of aliskiren was not affected by AT 1 receptor deletion (renal overexpression of renin) or Ren1c gene deletion (no renal renin expression).…”

Section: Discussionmentioning

confidence: 98%

The direct renin inhibitor aliskiren localizes and persists in rat kidneys

Feldman¹,

Jin²,

Han³

et al. 2013

American Journal of Physiology-Renal Physiology

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Characterization of renin mRNA expression and enzyme activity in rat and mouse mesangial cells

Cited by 23 publications

References 21 publications

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Activation of renal renin-angiotensin system in upstream stimulatory factor 2 transgenic mice

The direct renin inhibitor aliskiren localizes and persists in rat kidneys

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